This application addresses broad Challenge Area [15] Translational Science, and specific Challenge Topic, 15- LM-101: Presenting genome information in electronic health records. The advent of genome-scale measurements and health information technologies allows us to reconnect patient subjects and researchers in a manner respectful of regulations and privacy concerns and to maximize potential benefit to the public and the individual in the course of research. At the same time the relative passivity of the healthcare establishment, and the aggressive entry of direct-to-consumer companies into the genetic testing process have converged to create a growing expectation that complete disclosure of all interpretations of genome-wide variants is a public good and a means to maximize personal health. Unfortunately, our knowledge of the clinical import of genetic variants, whether common or rare, appears increasingly compromised, especially when applied to asymptomatic "well" individuals. Without the enrichment of prior probabilities based on family history or symptomatology or clinical evaluation, it appears likely that the incidentalome (the collection of all incidental findings due to comprehensive genetic testing) is likely to grow rapidly. The incidentalome presents a threat both to the health of individuals subject to unnecessary testing or treatment based on false positive testing and to society as it will increasingly discredit well-founded genomically informed personalized treatments if these are drowned out by the "noise" of unnecessary tests and procedures. Consequently, a means of carefully communicating that information which is accurate and actionable in an understandable fashion appears necessary to meet even the most basic criteria for "first do[ing] no harm." We propose here to complete the work on the Informed Cohort, a concept that we first articulated in an article in Science magazine in 2007, and that has built on our decade-long efforts in conceiving and building personally controlled health records (PCHR). In the Informed Cohort concept paper, we described a mechanism by which patients could be notified of genetic findings that were relevant to them after the notification had been first vetted by the Institutional Review Board (IRB) and the message had been formulated by a new adjunct to the IRB that we entitled the Informed Cohort Oversight Board (ICOB). The Informed Cohort messaging mechanism employs PCHR infrastructure to allow messages to be precisely targeted to only the relevant subjects while keeping the researchers fully ignorant of the identity of the subjects (i.e., preserving their anonymity) and enabling the subjects to decide whether or not to receive or act on these messages (i.e., preserving their autonomy). Moreover, the PCHR utilities in the Informed Cohort allow the subject to continue to add to the research database and to refine the phenotypic data and to contribute additional biomaterials. In this fashion, the Informed Cohort creates an ongoing increasingly refined research cohort while allowing the patients/subjects to personally benefit from their involvement. Our efforts to date have focused on the acquisition of data into the Informed Cohort structures. Here we focus on the outgoing messages from the researchers, via the IRB and ICOB to the patients. Practically, this means working on the tools that the ICOB requires to rapidly and efficiently construct messages for subjects and to create the notification mechanisms and user interfaces to ensure safe and targeted delivery of the Informed Cohort patient/subject-directed messages regarding the meaning of particular common or rare genomic variants. We propose to evaluate this functionality in formative study of 500 patients (children, a high priority population for NIH research) subject to genome-wide variant assays in our Developmental Medicine Center. The advent of genome-scale measurements and health information technologies allows us to reconnect patient subjects and researchers in a manner respectful of regulations and privacy concerns and to maximize potential benefit to the public and the individual in the course of research. We seek a positive impact on the public health by developing the technology and framework for carefully and selectively communicating relevant information which is accurate and actionable in an understandable fashion.